Abstract: Oral immunological tolerance is an essential although poorly understood phenomenon by which the immune system becomes "non-responsive" against antigens administered via the intestinal mucosa. Although this process is vital for the co-existence with non-pathogenic intestinal antigens, such as food and normal microbial flora, the mechanisms responsible for oral tolerance remain poorly understood. Lymphocyte migration (homing) is essential for protective and pathological immune responses and we and others have demonstrated that gut-associated antigen-presenting dendritic cells instruct lymphocytes to express gut-specific homing receptors, integrin 4[unreadable]7 and chemokine receptor CCR9, by a mechanism dependent on the vitamin A metabolite retinoic acid (RA). Importantly, RA also contributes to the generation of regulatory T lymphocytes (TREG), which have been shown to be important for the establishment of oral tolerance. Given that RA induces gut-homing lymphocytes and also promotes TREG differentiation, I hypothesize that RA is essential for the establishment of oral tolerance i) by inducing gut-tropism and "sequestering" potentially pathogenic T lymphocytes in the intestinal mucosa and ii) by promoting TREG differentiation in the gut. If successful, my work will highlight a new physiological role of gut-homing in the establishment of oral tolerance, providing also a straightforward approach to induce immune tolerance using RA, which could be used in the treatment of autoimmune diseases. Public Health Relevance: My research could provide a straightforward approach to treat autoimmune diseases, such as multiple sclerosis, diabetes, psoriasis and rheumatoid arthritis. It would also offer a simple method for boosting intestinal immune responses for vaccination purposes, such as in infections by Salmonella, rotavirus, and HIV.